Cell-based drug delivery systems offer the prospect of biocompatibility, large-loading capacity, long in vivo lifespan, and active targeting of diseased sites. However, these opportunities are offset by an array of challenges, including safeguarding the integrity of the drug cargo and the cellular host, as well as ensuring that drug release occurs at the appropriate time and place. Emerging strategies that address these, and related, issues, are described herein.

Laboratory safety has received heightened attention due to a series of devastatingly tragic accidents in both academic and nonacademic settings. Consequently, chemistry departments at various academic institutions now offer some form of formal training in laboratory safety for entering graduate students. Although the extent of this training varies widely among institutions, it typically includes an online assessment and/or minimal in-person classroom instruction. However, a significant gap exists between a lecture hall setting and the complex environment that comprises an advanced research laboratory. We've adapted the technological advances in virtual and augmented reality to bridge this gap. A set of 360°virtual reality lab experiences, highlighting safety infractions, have been created for a variety of subdiscipline-distinct (medicinal, organic, inorganic, physical, drug screening) laboratory settings. Notable features include the accurate depiction of the visual complexity associated with research settings, the opportunity for the trainee to explore multiple laboratories in a self-paced fashion, and immediate feedback with respect to the identification of safety hazards. The VR Lab Safety modules were very well received by first year graduate students, with greater than 85% of the respondents describing the VR experience as engaging and memorable, as a good supplement to safety reading material, and as providing real world examples that are otherwise difficult to visualize.

Arthritis is a leading cause of disability in adults, which can be intensely incapacitating. The location and intensity of the pain is both subjective and challenging to manage. Consequently, patient-directed delivery of anti-inflammatories is an essential component of future therapeutic strategies for the management of this disorder. The design and application of a light-responsive red blood cell (RBC)-conveyed dexamethasone (Dex) construct that enables targeted drug delivery upon illumination of the inflamed site is described. The red wavelength (650 nm) responsive nature of the phototherapeutic is validated using tissue phantoms mimicking the light absorbing properties of various skin types. Furthermore, photoreleased Dex has the same impact on cellular responses as conventional Dex. Murine RBCs containing the photoactivatable therapeutic display comparable circulation properties as fluorescently labeled RBCs. In addition, a single dose of light-targeted Dex delivery is fivefold more effective in suppressing inflammation than the parent drug, delivered serially over multiple days. These results are consistent with the notion that the circulatory system be used as an on-command drug depot, providing the means to therapeutically target diseased sites both efficiently and effectively.

Cobalamin has shown promise as a light-sensitive drug delivery platform owing to its ease of modification and the high quantum yields for drug photorelease. However, studies to date on the general photochemistry of alkyl cobalamins have primarily focused on methyl and adenosyl-substituted derivatives, the natural cofactors present in various enzymatic species. We describe the synthesis and photolytic behavior of cobalamin conjugates comprised of different combinations of fluorophores and β-axial ligands. In general, cobalamin conjugates containing β-axial alkyl substituents undergo efficient photolysis under aqueous conditions, with quantum yields up to >40%. However, substituents that are large and hydrophobic, or unable to readily support the presumed radical intermediate, suffer less efficient photolysis (<15%) than smaller, water-soluble, analogs. By contrast, quantum yields improve by 2-fold in DMF for cobalamins containing large hydrophobic β-axial substituents. This suggests that drug release from carriers comprised of membranous compartments, such as liposomes, may be significantly more efficient than the corresponding photorelease in an aqueous environment. Finally, we explored the impact of fluorophores on the photolysis of alkyl cobalamins under tissue-mimetic conditions. Cobalamins substituted with efficient photon-capturing fluorophores display up to 4-fold enhancements in photolysis relative to unsubstituted derivatives. In summary, we have shown that the photosensitivity of alkyl cobalamin conjugates can be tuned by altering the Co-appended alkyl moiety, modulating the polarity of the environment (solvent), and installing photon-capturing fluorophores onto the cobalamin framework.

Introduction 50 million patients are diagnosed with arthritis yearly, with a total of 20% of the nation suffering from this ailment. No curative treatment for arthritis currently exists, only therapeutics that mitigate its symptoms while inducing severe side effects from chronic systemic exposure. The current inadequacy of treatment highlights the need for innovative drug delivery methods. We have developed a photosensitive method of drug delivery that can be spatiotemporally controlled to treat arthritis and reduce systemic exposure to therapeutics, such as dexamethasone, that cause severe side effects. We hypothesize that by conveying a photo‐responsive vitamin B12‐dexamethasone (B12‐dex) conjugate within red blood cells (RBCs) we will be able to localize delivery of dex, treat arthritis with an overall lower amount of dex, and diminish systemic exposure. Methods and Results Alkyl‐cobalamin derivatives of vitamin B12 are known to contain an intrinsically photosensitive axial cobalt‐carbon bond. We employed this property to create a light responsive drug platform that is conveyed throughout the circulatory system by RBCs. First, we have demonstrated that the B12‐drug phototherapeutic agents can be loaded via a hypotonic swelling protocol and trapped within RBCs due to the membrane impermeability of B12. Second, we installed a Cy5 “antenna” on B12, enabling the phototherapeutic to respond to long wavelength (650 nm) tissue‐penetrating light. Third, we employed intravital imaging to demonstrate that RBC‐conveyed phototherapeutics are retained in circulation for up to 2 hours, whereas free B12‐drug conjugates rapidly diffuse into surrounding tissue. Building off of these results, we synthesized and loaded a B12‐dex conjugate into RBCs and investigated the therapeutic efficacy of this agent using a collagen antibody induced mouse model of arthritis. Arthritic mice were treated with intraperitoneal (IP) dex at a standard dose, B12‐dex RBCs, and B12‐water RBCs. Dex or water from B12‐drug RBCs was released locally to the arthritic paw via a 650 nm 3 mW laser. As expected, standard of care dex caused arthritis to go into remission while B12‐water RBCs did not treat arthritis. However, B12‐dex RBCs also successfully induced remission of arthritis with a 3‐fold lower dose of dex relative to IP dex. Thus, we successfully treated arthritic mice using B12‐dex RBCs while systemically delivering a much lower dose to achieve comparable remission to IP dex treatment. Conclusions We have demonstrated that B12‐dex, conveyed by RBCs, offers a novel method for the treatment of arthritis. This technology potentially addresses three key limitations of current arthritis therapy: (1) the inability to selectively deliver high quantities of a drug to the inflamed joint, (2) moderate to severe systemic side effects from long‐term exposure, and (3) the inability to direct therapeutics in a patient‐directed fashion. Future work will further probe the issue of selectivity and side effects by investigating the therapeutic index of B12‐dex as ...